Necrotizing enterocolitis (NEC) has emerged as the most common gastrointestinal emergency in neonatal intensive care units (NICU). A. M. Kosloske, "Epidemiology of necrotizing enterocolitis," Adcta Paediatr. Suppl. 396:2 (1994). U. G. Stauffer, "Necrotizing enterocolitis," Acta Paediatr 83:666 (1994). NEC can occur endemically as isolated cases, or at times, epidemic clusters of cases are seen in neonatal nurseries. In the United States the incidence ranges from 1 to 3 per 1000 live births and roughly 1 to 7.7% of NICU admissions. R. C. Holman et al., "Necrotizing Enterocolitis Mortality in the United States, 1979-85" AJPH 79:8 (1989). The average annual mortality rate for NEC was 13.1 deaths per 100, 000 live births. In the United States, about 12,000 newborn infants per year develop NEC, with a mortality rate of up to 40%. Clinically, NEC is characterized by a triad of symptoms: abdominal distention and tenderness, gastrointestinal bleeding, and pneumatosis intestinalis, i.e., air within the intestinal wall. R. M. Kliegman and A. A. Fanaroff, "Necrotizing Enterocolitis" New Eng. J. Med. 310:1093 (1984). Death associated from NEC occurs from intestinal perforation with sepsis with shock, intravascular dissemination, pneumatosis, and short bowel syndrome resulting in malabsorption after resection.
The etiology and pathogenesis of NEC are unclear. Epidemiological studies point to (1) tissue injury or GI tract immaturity (2) infection, (3) oral feeding and (4) hypoxia. A. M. Kosloske, "A unifying hypothesis for pathogenesis and prevention of necrotizing enterocolitis" J. Pediatrics 117:S68 (1990). It is thought that an opportunistic member of the infants microbial flora in combination with tissue injury and/or gastrointestinal immaturity initiates the disease. The reduction in gut barrier function leads to the translocation of bacterial toxins, such as endotoxin, i.e., lipopolysaccride (LPS) or exotoxins. The increased local levels of these substances in the intestinal mucosa can then trigger a series of host responses and stimulate the production of proinflammatory phospholipids and/or cytokines such as platelet activating factor (PAF), tumor necrosis factor (TNF) and interleukins 1 and 6 (IL-1 and IL-6). W. Hsueh et al., "Interaction of Inflammatory Cytokines, Bacterial Products, and Lipid Mediators in Intestinal Injury" In: Cytokines in Health and Disease (2d Edition, eds. Remeck, Daniel G & Friedland, J.) (Marcel Dekker, Inc, NY, N.Y. 1997) (pgs. 427-443). These secreted factors can then cause local or systemic effects such as endotoxemia, intravascular coagulation and hypoxia. The oral feeding, thought to supply the offending microbe with a nutritional substrate, allows further intestinal colonization. Indeed, infant formula, which promotes malabsorption and is devoid of immunoprotective factors, is implicated in the pathogenesis of NEC. With a supply of substrate, events can progress rapidly, leading to death for a high percentage of infants with NEC.
There have been very few controlled studies of the various recommended treatment protocols for NEC. Since there is strong circumstantial evidence that NEC is initially caused by an infectious agent, antibiotics are used as a first line of defense. As soon as the disease is suspected, all enteral feeding is discontinued, and the infant is fed by parenteral alimentation. Parenteral broad-spectrum antibiotics such as carbenicillin or ticarcillin in combination with a second parenteral aminoglycoside such as gentamycin is then usually given. Ch. Fast and H. Rosegger, "Necrotizing enterocolitis prophylaxis, oral antibiotics and lyophilized entero-bacteria vs oral immunoglobulins" Acta Paediatr Suppl 396:86 (1994). Treatment periods typically last for 3 to 10 days. Drawbacks to these procedures, beyond the inability for them to work in 20-40% of the NEC cases are numerous. The aminoglycoside therapy requires monitoring if treatments are &gt;3 days to avoid ototoxicity and nephrotoxicity. These broad-spectrum antibiotics can disrupt the establishment of the normal flora in the infant, important for proper nutrition and preventing opportunistic infections. A further potential danger is that the non-selectivity of antibiotics can promote widespread drug resistance in intestinal organisms, such as Enterococcus and Staphylococcus aureus whereas at present only one antibiotic is effective against them.
Apart from antibiotic use, another serious complication of the current treatment protocol is that removing the infant from enteral feedings can markedly influence gastrointestinal maturity. Enteral feedings stimulate a series of gut hormones such as motilin, gastrin and enteroglucagon which are important regulators of gastrointestinal function and mucosal growth. This increase of local "gut "hormones does not occur in infants fed with intravenous alimentation. Alterations of gut hormone physiology during prolonged periods of abstinence from enteric alimentation may place the immature intestine in jeopardy for mucosal atrophy, feeding intolerance and carbohydrate malabsorption. Accordingly, the sooner the patient receives enteral feedings the greater the chance of preventing the adverse effects of parenteral nutrition. At this point, a safer, more selective and effective therapeutic for NEC is desired.
Newer approaches to treat NEC have focused on prevention rather than treatment. Success thus far with newer approaches has been limited. Several studies have looked to determine if human breast milk feeding could possibly protect against the development of NEC. Human milk has many immunoprotective components such as lysozyme, PAF acetylhydrolase and immunoglobulin. Unfortunately, the studies have been inconclusive, and it appears that this approach does not decrease the severity and incidence of NEC. The use of human serum IgA-IgG administered orally to low-birth weight infants has been reported to have some benefit. M. M. Eibl et al., "Prevention of Necrotizing Enterocolitis in Low-Birth-Weight Infants by IgA-IgG Feeding" New Eng. J Med. 319:1 (1988). H. M. Wolf and M. M. Eibl, "The Relevance of Immunoglobulin in the Prevention of Necrotizing Enterocolitis," In: Immunology of Milk and the Neonate (Plenum Press, NY 1991). H. M. Wolf and M. M. Eibl, "The anti-inflammatory effect of an oral immunoglobulin (IgA-IgG) preparation and its possible relevance for the prevention of necrotizing enterocolitis," Acta Paediatr Suppl. 396:37 (1994).
Problems with these therapies may stem from the fact that the active ingredients or important antibody specificities in these treatments are unknown. This makes it very difficult to manufacture them consistently and reproducibly from preparation to preparation and achieve similar outcomes.
Recent studies have suggested that certain proinflammatory molecules including PAF, LPS and cytokines such as, TNF and IL-6 play an important role in the development of NEC in the newborn. Patients with NEC were reported to have higher levels of TNF, IL-1 and IL-6. D. Birk et al., "Is the elimination of endotoxin and cytokines with continuous lavage an alternative procedure in necrotizing enterocolitis?" Acta Paediatr Suppl. 396:24 (1994). Animal models for NEC indicate that the pathology associated with NEC can be generated by the administration of PAF, as well as various endotoxins and cytokines. W. Hsueh et al., "Platelet-activating factor: an endogenous mediator for bowel necrosis in endotoxemia," FASEB J. 1:403-405 (1987). X. Sun and W. Hsueh, "Bowel Necrosis Induced by Tumor Necrosis Factor in Rats Is Mediated by Platelet-activating Factor," J. Clin. Invest. 81:1328 (1988). Pretreatment of animals with a PAF antagonist, PAF-AH, has been shown to modify the development of NEC. M. Caplan et al., "The Role of Recombinant Platelet-Activating Factor Acetylhydrolase in a Neonatal Rat Model of Necrotizing Enterocolitis," Ped. Research 42:779 (1997). Interestingly, human milk has significant PAF-AH activity, whereas neonatal formulas have no measurable PAF-AH enzyme function. This difference may contribute to the lower incidence of NEC in breast milk-fed neonates.
Clearly there is a great need for agents capable of preventing and treating NEC. It would be desirable if such agents could be administered in a cost-effective and timely fashion, with a minimum of adverse side effects.